Abstract Racial health disparities persist among black and white women for colorectal cancer (CRC). Since the gut microbiota has been linked to CRC, understanding racial differences in the gut microbiota may yield new insight into unexplained disparities in CRC incidence. Generally healthy non-Hispanic black or white females who were at least 19 years old provided survey data, anthropometrics, and stool samples. Fecal DNA was collected and isolated from a wipe. PCR was used to amplify the V4 region of the 16SrRNA gene and 250 bases were sequenced using the MiSeq platform. Microbiome data were analyzed using the QIIME package. OTU data were log transformed and normalized. Linear models in R Package “limma” were used to test statistical significance differences. Fecal samples were analyzed for 80 females (47 black, 33 white). Mean age and BMI were 39.9 years and 30.1 kg/m2, respectively. Blacks had a higher average BMI than whites (33.3 vs. 27.5 kg/m2; p<0.01) and larger waist circumference (98.3 vs. 86.6 cm; p<0.01). Unadjusted comparisons revealed no racial differences in alpha diversity. Racial differences were observed in beta diversity and abundance of top-10 OTUs. Blacks had higher abundances than whites of Faecalibacterium (p=0.03) and Bacteroides (p=0.04). The association between race and Bacteroides (logFC=1.72; 0=0.02) persisted in fully adjusted models. Black race was associated with a higher abundance of Bacteroides, which has been linked to CRC. Other racial differences in the gut microbiota were also observed. Efforts to cultivate an “ideal” gut microbiota may help reduce CRC risk and health disparities. Citation Format: Tiffany L. Carson, Fuchenchu Wang, Xiangqin Cui, Bradford E. Jackson, Liam Van Der Pol, Elliot J. Lefkowitz, Casey Morrow, Monica Baskin. Racial comparisons of the gut microbiota of generally healthy black and white women for insights into colorectal cancer disparities [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr A59.
Background: Recent clinical guidelines for adults with neurological disabilities suggest the need to assess measures of static and dynamic balance using the Berg Balance Scale (BBS) and Dynamic Gait Index (DGI) as core outcome measures. Given that the BBS measures both static and dynamic balance, it was unclear as to whether either of these instruments was superior in terms of its convergent and concurrent validity, and whether there was value in complementing the BBS with the DGI. Objective: The objective was to evaluate the concurrent and convergent validity of the BBS and DGI by comparing the performance of these two functional balance tests in people with multiple sclerosis (MS). Methods: Baseline cross-sectional data on 75 people with MS were collected for use in this study from 14 physical therapy clinics participating in a large pragmatic cluster-randomized trial. Convergent validity estimates between the DGI and BBS were examined by comparing the partial Spearman correlations of each test to objective lower extremity functional measures (Timed Up and Go (TUG), Six-Minute Walk Test (6MWT), Timed 25-Foot Walk (T25FW) test) and the self-reported outcomes of physical functioning and general health using the 36-Item Short Form Health Survey (SF-36). Concurrent validity was assessed by applying logistic regression with gait disability as the binary outcome (Patient Determined Disease Steps (PDDS) as the criterion measure). The predictive ability of two models, a reduced/parsimonious model including the BBS only and a second model including both the BBS and DGI, were compared using the adjusted coefficient of determinations. Results: Both the DGI and BBS were strongly correlated with lower extremity measures overall as well as across the two PDSS strata with correlations. In PDDS ≤ 2, the difference in the convergence of BBS with TUG and DGI with TUG was −0.123 (95% CI: −0.280, −0.012). While this finding was statistically significant at a type 1 error rate of 0.05, it was not significant (Hommel’s adjusted p-value = 0.465) after accounting for multiple testing corrections to control for the family-wise error rate. The BBS–SF-36 physical functioning correlation was at least moderate and significant overall and across both PDDS strata. However, the DGI–physical functioning score did not have a statistically significant correlation within PDDS ≤ 2. None of the differences in convergent and concurrent validity between the BBS and DGI were significant. The additional variation in 6MWT explained by the DGI when added to a model with the BBS was 7.78% (95% CI: 0.6%, 15%). Conclusions: These exploratory analyses on data collected in pragmatic real-world settings suggest that neither of these measures of balance is profoundly superior to the other in terms of its concurrent and convergent validity. The DGI may not have any utility for people with PDDS ≤ 2, especially if the focus is on mobility, but may be useful if the goal is to provide insight on lower extremity endurance. Further research leveraging longitudinal data from pragmatic trials and quasi-experimental designs may provide more information about the clinical usefulness of the DGI in terms of its predictive validity when compared to the BBS.
The objective of this study is to investigate risk factors and disease burden in pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP).
Diabetes due to pancreatic ductal adenocarcinoma (PDAC-D) is often difficult to clinically distinguish from type 2 diabetes (T2D) and both insulin resistance and reduced insulin secretion have been implicated in its pathophysiology. Although these metabolic defects are similar to those seen in T2D, the degree to which they relatively contribute to hyperglycemia in PDAC-D has not been established. Additionally, there is a lack of understanding of alpha cell function in PDAC-D. We sought to address these gaps in the DETECT study (NCT03460769). Adults with PDAC-D (n=28) or T2D (n=99) (diabetes diagnosis <3 years) underwent a standardized liquid mixed-meal tolerance test with serum glucose, insulin, and glucagon measurements. Insulin sensitivity was assessed by the Matsuda index, insulin secretion by the insulinogenic index, and beta cell function by the oral disposition index. The mean duration of diabetes was 10.8 months in PDAC-D and 12.5 months in T2D (P=0.51). HbA1c was higher in PDAC-D (7.27% vs 6.58%, P=0.03). The area under the curve (AUC) of the glucose response was similar in PDAC-D vs T2D (232 vs. 238 mg.min/ml, P=0.08). Insulin sensitivity was 2.5x higher in PDAC-D than in T2D (3.65 vs 1.45, P<0.001). In contrast, insulin secretion was 81% lower in PDAC-D (18 vs 95 μU/mg, P<0.001), and the oral disposition index was 40% lower (0.80 vs. 1.32, P<0.001). Fasting glucagon was similar in PDAC-D and T2D (21.1 vs 17.7 pM, P=0.09). In both groups, glucagon rose after the meal, but the incremental AUC was 57% higher in PDAC-D (581 vs. 370 pM.min, P=0.01). These results suggest that impaired insulin secretion is considerably more important than insulin resistance in the etiology of hyperglycemia of PDAC-D and that post-prandial alpha-cell dysregulation is likely to play a greater role than previously recognized. Collectively, these data also suggest that targeting insulin and glucagon levels, rather than insulin resistance, may be a more effective strategy to treat PDAC-D. Disclosure F.G.S.Toledo: Research Support; Dompé. R.V.Considine: Research Support; Lilly Diabetes. S.T.Chari: Advisory Panel; Nestlé Health Science, Guardant, Bluestar genomics. S.C.Graham: None. D.K.Andersen: None. J.Rinaudo: None. J.Serrano: None. M.O.Goodarzi: Advisory Panel; Nestlé Health Science, Other Relationship; Nestlé Health Science. P.Hart: Consultant; Sagent Pharmaceuticals. On behalf of the cpdpc: n/a. Y.Li: Stock/Shareholder; Agenus, Inc. F.Wang: None. D.Yadav: None. M.Bellin: Consultant; Insulet Corporation, Vertex Pharmaceuticals Incorporated, Research Support; Dexcom, Inc., ViaCyte, Inc. K.Cusi: Consultant; Poxel SA, Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, 89bio, Inc., Bristol-Myers Squibb Company, Lilly, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Medscape, Myovant, Novo Nordisk, ProSciento, Quest Diagnostics, Sagimet, Sonic Incytes, Terns, Research Support; Echosens, Inventiva, LabCorp, Zydus. W.E.Fisher: None. Y.C.Kudva: Advisory Panel; Novo Nordisk, Research Support; Dexcom, Inc. W.Park: Advisory Panel; AbbVie Inc., Ariel Medicine, Nestlé Health Science, Consultant; Arctx Medical, Craif, Research Support; AbbVie Inc., Stock/Shareholder; Arctx Medical. Funding National Institutes of Health (U01DK108306, U01DK108288, U01DK108320, U01DK108323, U01DK108326, U01DK108327, U01DK108328, U01DK108300, U01DK108314, U01DK126300)
Abstract Background: Low molecular weight cyclin E (LMW-E) are oncogenic forms of cyclin E that are post translationally generated from the full-length cyclin E1 (FL-cycE). LMW-E is detected in breast cancer cells and tumor tissues, but not in normal mammary epithelial cells or adjacent normal tissues. Unlike FL-cycE, LMW-E drives mammary epithelial cell transformation in human cells and spontaneous mammary tumor formation in transgenic mouse models, but the oncogenic mechanisms of LMW-E and its unique function(s) independent of FL-cycE are not fully understood. It is currently assumed that LMW-E drives the tumorigenic process by promoting G1/S cell cycle transition and accelerating mitotic exit. Biochemical features such as longer protein half-life, higher affinity to its kinase partner CDK2, and resistance to endogenous CDK inhibitors such as p21 and p27 all promote the tumorigenic ability of LMW-E. Clinical studies in breast cancer reveal that overexpression of LMW-E predicts recurrence and poor survival in breast cancer patients independent of molecular subtype, Ki67 status, nodal status, or tumor grade, suggesting LMW-E may drive breast cancer development independent of its role in cell proliferation. In the current study, we tested the hypothesis that LMW-E promotes genomic instability by deregulating DNA replication and damage repair. Results: We generated immortalized pre-cancerous human mammary epithelial cells (hMECs) to express doxycycline inducible LMW-E or FL-cycE in CCNE1 knock-out background. We found that FL-cycE overexpression led to DNA replication stress and DNA damage accumulation, resulting in reduced cell viability. LMW-E overexpression, on the other hand, promoted cell survival under replication stress, resulting in persistent genomic instability. RNA-sequencing results showed LMW-E but not FL-cycE overexpression enhanced DNA replication and damage repair pathways. Molecularly, LMW-E interacted with and facilitated pre-replication complex assembly. LMW-E also mediated DNA repair by upregulating RAD51 and C17orf53, showing a dominant repairing effect over DNA damage induced by FL-cycE. Moreover, targeting the replication stress response pathway ATR-CHK1-RAD51 with small molecule inhibitors significantly decreased viability of LMW-E overexpressing hMECs and breast cancer cells. Lastly, we showed that positive LMW-E status was associated with genomic instability in tumors from a cohort of 725 patients diagnosed with early-stage breast cancer, further supporting our hypothesis that LMW-E promotes genomic instability to fuel breast cancer development. Conclusions: Collectively, our findings delineated a novel role for LMW-E in breast tumorigenesis mediated by replication stress tolerance and genomic instability, providing novel therapeutic strategies for LMW-E overexpressing breast cancers. Citation Format: Mi Li, Spiridon Tsavachidis, Fuchenchu Wang, Tuyen Bui, Tuyen D. Nguyen, Linjie Luo, Asha S. Multani, Melissa L. Bondy, Kelly K. Hunt, Khandan Keyomarsi. Low molecular weight cyclin E deregulates DNA replication and damage repair to promote genomic instability in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 308.
Racial health disparities persist among black and white women for colorectal cancer. Understanding racial differences in the gut microbiota and related covariates (e.g., stress) may yield new insight into unexplained colorectal cancer disparities.
